Andrea AmbrosiDenmark group meeting

November 18, 2014

Jung, M. E.; Piizzi, G. Chem. Rev. 2005, 105, 1735.

Definition

The Thorpe-Ingold effect (a.k.a. gem-dialkyl effect) is the name given to theacceleration of a cyclization due to the replacement of hydrogen atoms withalkyl groups on the carbons tethering the two reacting centers.

Proposed explanations:

Angle compression

Thermodynamic factors

Kinetic factors

Forbes, M. D. E. et al. J. Am. Chem. Soc. 1992, 114, 10978.

Illustrative examples

Schrock cat.

neat, 25 C

O

mixture of oligomers

Schrock cat.

neat, 25 C

O

Me Me Me Me

95%

OMe

Me MeMe

Newman, M. S.; Harper, R. J. J. Am. Chem. Soc. 1958, 80, 6350.

HCl 0.003 M

dioxane/H2O, 30 C1

OO

R R

O

OH OH

H H

0.066OH OH

Me Me

0.029OH OH

Et Et

0.011OH OH

iPr iPr

relativerate

Pete, J.-P. Chem. Commun. 1998, 235.

h

CH3CN, 25 C

52%

no reaction

O

O

O

h

CH3CN, 25 C

O

O

O

Me Me

OH

OOMe

Me

Natural products

Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc., Trans. 1915, 107, 1080.

Internal angle reduction (Thorpe-Ingold, 1915)

‘There must be a greater tendency to form ring-compoundsfrom the cyclic structure, owing to the closer proximity ofthe groups attached to the carbon atoms of the side chains,through the agency of which the ring-formation is effected.’

α > β

Jocelyn Field Thorpe(1872-1939)

Christopher Kelk Ingold(1893-1970)

Ingold, C. K.; Sako, S.; Thorpe, J. F. J. Chem. Soc., Trans. 1922, 121, 1177.

Internal angle reduction (Thorpe-Ingold, 1922)

Jung, M. E.; Piizzi, G. Chem. Rev. 2005, 105, 1735;Jager, J.; Graafland, T.; Schenk, H.; Kirby, A. J.; Engberts, J. B. F. N. J. Am. Chem. Soc. 1984, 106, 139.

Internal angle reduction

Substitution of the methylene hydrogens with the more stericallydemanding alkyl groups produces a compression of the internal angleθ. As a result, the two reactive units X and Y move close together,and this facilitates the cyclization.

θ1 > θ2 > θ3

HOOC SO2NMePh

H H

HOOC SO2NMePh

H Et

110.4 107.4HOOC SO2NMePh

Me Me

HOOC SO2NMePh

Et Et

105.0 105.3

Confirmed by X-ray measurements

Rate of hydrolysis

Nilsson, H.; Smith, L. Z. Phys. Chem. 1933, 166A, 136.

Cyclization of chlorohydrines

HOCl

HOCl

1 5.5Me

HOCl

HOCl

21 248

Me

Me

Me

HOCl

HOCl

252 1360Me

HOCl

HOCl

2040 11600

Me

Me

Me

Me Me Me Me

Me Me

Me Me

relativerate

Brown, R. F.; Van Gulick, N. M. J. Org. Chem. 1956, 21, 1046.

Cyclization of bromobutylamines

1relative

rate

BrNH2

2.19

BrNH2

Me Me158

BrNH2

Me Me

594

BrNH2

9190

BrNH2

5250

BrNH2

Ph PhEt Et iPr iPr

0.158

BrNH2

Me Me

Geminal alkyl substitution affects the distribution of rotamers due to non-bondedinteractions with the chain, favoring the coiled configurations and increasing theprobability of cyclization.

von Ragué Schleyer, P. J. Am. Chem. Soc. 1961, 83, 1368.

Contribution of angle compression

Contribution of angle compression:

2.15 kcal/mol

Contribution of angle compression:

0.16 kcal/mol

The angle compression has a great influence on reaction involving small rings, but plays a minor role with larger rings.

Allinger, N. L.; Zalkow, V. J. Org. Chem. 1960, 25, 701.

Thermodynamic analysis (Allinger-Zalkow, 1960)

Reaction ΔH°(kcal/mol)

ΔS°(cal/K·mol)

Keq

10.5 9.7 2.4·10-7

10.5 15.9 5.0·10-5

9.4 13.9 1.4·10-4

MeMe + H2

2 gauche interactions 8 gauche interactions

Me Me MeMe

Due to the increased number of gauche interactions in the open-chain substrate,the enthalpy favors ring closure of substituted hexanes.

Because branching reduces the rotation in the open-chain more than in the ring,the entropy also favors ring closure.

Allinger, N. L.; Zalkow, V. J. Org. Chem. 1960, 25, 701.

Thermodynamic analysis (Allinger-Zalkow, 1960)

The pronounced effect of alkyl substituents in favoring cyclization is due in part to an enthalpic effect and in part to an entropic effect.∆ ° ∆ ° ∆ °

decreases increases

If cyclization is the rate-determining step, these arguments can be translated to the kinetic terms ∆ ‡ and ∆ ‡ and to the rate of cyclization.

Benedetti, F.; Berti, F.; Fabrissin, S.; Gianferrara, T.; Risaliti, A. J. Org. Chem. 1991, 56, 3530.

Cyclization of γ-epoxy bis-sulfones

The observed rates are the result of an equilibrium governed by gem-dimethyl

repulsions and gauche interactions.

1relativerate

PhO2S

SO2Ph

H

HO

H H

1.7

PhO2S

SO2Ph

H

HO

H Me

23

PhO2S

SO2Ph

H

HO

Me Me

0.039

PhO2S

SO2Ph

Me

HO

H H

0.81

PhO2S

SO2Ph

H

MeO

H H

no reaction

PhO2S

SO2Ph

Me

MeO

H H

inhibited by trajectory of backside attack

independently made

Bruice, T. C.; Pandit, U. K. J. Am. Chem. Soc. 1960, 82, 5858.

Kinetic analysis (Bruice-Pandit, 1960)

The increased rate of anhydride formation is attributed to an increase in theprobability of the profitable rotamer distributions in which the reactinggroups are close to each other.

Bruice, T. C.; Pandit, U. K. J. Am. Chem. Soc. 1960, 82, 5858Jung, M. E.; Piizzi, G. Chem. Rev. 2005, 105, 1735.

Kinetic analysis (Bruice-Pandit, 1960)

Unsubstituted

Substituted

reactive rotamer

unreactive rotamer

equally populated

Substitution results in an increase in the population of the reactive rotamers with the two ends properly oriented for cyclization, due to an increase in the ground state energy.

Wilson, S. R.; Guarnieri, F. Tetrahedron Lett. 1991, 32, 3601.

Conformational analysis

Calculations of rotational states show an increase of the population of the gauche conformers upon substitution, even at low temperatures.

Jung, M. E. Synlett 1990, 1990, 186.

Angle compression or Reactive rotamer?

‘There is good experimental evidence for this anglecompression, but it is relatively small. Thus we (and others)did not believe that the angle compression would be a majorcontributing factor in the increase in cyclization rates, but upuntil this time there was no experimental evidence toconfirm this hypothesis.’

‘Dimethyl substitution on a central methylene should produce both the reactive rotamereffect and the angle compression, and thus it would be impossible to distinguish between thetwo. So one had to devise a system that forced the two effects to be in opposition.’

Michael E. Jung

Jung, M. E.; Gervay, J. J. Am. Chem. Soc. 1991, 113, 224.

Intramolecular Diels-Alder (Jung)

Angle compression is not an important factor in gem-dialkyl effect. The acceleration arises from conformational effects.

Angle compression comparable to dihydroReactive rotamer much faster than dihydro

Jung, M. E.; Gervay, J. J. Am. Chem. Soc. 1991, 113, 224.

Intramolecular Diels-Alder (Jung)

Substrate ΔH≠

(kcal/mol)ΔS≠(cal/K·mol)

ΔG≠

(kcal/mol)

19.8 -22.7 26.6

18.4 -23.2 25.3

14.9 -24.0 22.1

17.3 -26.6 25.2

16.3 -23.9 23.4

O

O

COOMe

HH O The acceleration is mostly an enthalpic

effect.

The entropic term is negative and wouldtherefore retard the reaction.

Cyclic substituents are less effective thangem-dimethyl because of the additionalstrain introduced by the ring.

Sternbach, D. D.; Rossana, D. M.; Onan, K. D. Tetrahedron Lett. 1985, 26, 591.

Intramolecular Diels-Alder (Sternbach)

Angle compression is not the cause of the acceleration.

Heteroatoms minimize the developing eclipsing interactions and favor the rotationto the reactive rotamer.

Parrill, A. L.; Dolata, D. P. Tetrahedron Lett. 1994, 35, 7319.

Facilitated transition hypothesis (Dolata, 1994)

Challenged the reactive rotamer effect bycalculating the ground-state and transition-stateconformations for the IMDA studied by Jung.

If the reactive rotamer was the major contributor tothe gem-dialkyl effect, a plot of rate vs reactiverotamer population should result in a linearcorrelation.

A linear relationship was found between rate andcalculated ∆ ‡.

Rate enhancement depends on reduction of∆ ‡ and not upon the relative concentrationof reactive rotamers.Substitution lowers ∆ ‡ by destabilizing theground state more than the transition state.

Bachrach, S. M. J. Org. Chem. 2008, 73, 2466.

Lowering of ring-strain energy (Bachrach, 2008)

The gem-dialkyl effect has a thermodynamic component relatedto the lowering of ring strain energy upon substitution.

Thorpe-Ingold effect in organometallics – Group problem

Explain how the different bidentate phosphines will affect the rate of reductive elimination and why.

Thorpe-Ingold effect in organometallics – Group problem

Substituted phosphines inhibit the reductive elimination by shifting the pre-dissociation equilibrium to the left.

Arthur, K. L.; Wang, Q. L.; Bregel, D. M.; Smythe, N. A.; O'Neil, B. A.; Goldberg, K. I.; Moloy, K. G. Organometallics 2005, 24, 4624.

Formation of medium and large rings

The gem-dimethyl effect decreases as the ring size increases.Enthalpic and entropic effects become less important when large, strainless rings are formed.

Galli, C.; Giovannelli, G.; Illuminati, G.; Mandolini, L. J. Org. Chem. 1979, 44, 1258.

gem-difluorination

Several factors (kinetic/thermodynamic)

are invoked to explain acceleration.

Urbina-Blanco, C. A.; Skibinski, M.; O'Hagan, D.; Nolan, S. P. Chem. Commun. 2013, 49, 7201.

θ > 109.5° Eanti < Egauche θprod = 119° σCHσ*CF

θ < 109.5° Eanti > Egauche θprod = 113.5°

θ > 109.5° Eanti ≈ Egauche θprod = 115.8°

σCHσ*CO

Thorpe-Ingold effect in total synthesis

Kim, H.; Park, Y.; Hong, J. Angew. Chem. Int. Ed. 2009, 48, 7577.

- only 92%

3(dr = 10:1)

1 94%

only(dr > 20:1)

- 94%SS

Thorpe-Ingold effect in total synthesis

Kim, C. H.; Jang, K. P.; Choi, S. Y.; Chung, Y. K.; Lee, E. Angew. Chem. Int. Ed. 2008, 47, 4009;Eey, S.; Lear, M. J. unpublished results.

R = CH2OMeCH2OBnCH2OMOMvinylCH2CH2CON(OMe)Me

R = CN

Trimethyl lock effect

A severe conformational restriction of the side chain facilitates cyclization by eliminating non-productive isomers (stereopopulation control).

Winans, R. E.; Wilcox, C. F. J. Am. Chem. Soc. 1976, 98, 4281.

Trimethyllock

1relative

rate

OHCOOH

H

HH

1

OHCOOH

Me

HH

4400

OHCOOH

H

MeMe

Relief of ground-state strain upon cyclization.

Milstien, S.; Cohen, L. A. J. Am. Chem. Soc. 1972, 94, 9158.

5.1 1011

OHCOOH

Me

MeMe

Trimethyl lock in pro-drugs

Ueda, Y.; Mikkilineni, A. B.; Knipe, J. O.; Rose, W. C.; Casazza, A. M.; Vyas, D. M. Bioorg. Med. Chem. Lett. 1993, 3, 1761.

Paclitaxel (Taxol®)

Low water solubility (2 μg/mL)

Requires solubilizing agents (castor oil/ethanol)

Higher water solubility (>10 mg/mL)

Antitumor activity comparable to paclitaxel

Trimethyl lock in pro-drugs

Greenwald, R. B.; Choe, Y. H.; Conover, C. D.; Shum, K.; Wu, D.; Royzen, M. J. Med. Chem. 2000, 43, 475.

Daunorubicin

PEG (poly ethylene glycol) provides:

Water solubility

Targeted delivery to cancer tissues

Lower renal clearance

Summary

Several theories have been proposed to explain the source of rate-enhancement in the cyclization of gem-disubstituted systems.

This phenomenon appears to be complex; different factors can account forits origin depending upon the system under examination.

Regardless of its origin, there is little doubt that the Thorpe-Ingold effect isan important tool for synthetic chemists.

References

Effective Molarities for Intramolecular ReactionsKirby, A. J. Adv. Phys. Org. Chem. 1981, 17, 183-278

gem-Disubstituent Effect: Theoretical Basis and Synthetic ApplicationsJung, M. E.; Piizzi, G. Chem. Rev. 2005, 105, 1735-1766

Substituent and Solvent Effects in Intramolecular Diels-Alder Reactions

Jung, M. E. Synlett 1990, 186-190.

Trimethyl lock: a trigger for molecular release in chemistry, biology, and pharmacologyLevine, M. N.; Raines, R. T. Chem. Sci. 2012, 3, 2412-2420